The overall objective of this project is to understand and predict flow properties of blood in microvessels, in terms of the mechanical properties of individual red blood cells. The flow properties of blood are crucial both to the role of the circulation in mass transport to and from tissues, and to the mechanical load on the heart resulting from peripheral resistance. Red cells encounter continually changing vascular geometries as they traverse the microcirculation, resulting in transient motions and deformations. The effects of these transient motions and deformations on microvascular blood rheology will be investigated. The specific aims are: 1. To develop theoretical models for the transient motion and deformation of red blood cells in non-uniform passageways in the microcirculation, including capillaries with varying or irregular cross- sections and microvessels partially occluded by slowly moving or stationary leukocytes. The contribution of transient effects to flow resistance will be estimated. 2. To develop theoretical models for the transient motion and deformation of red blood cells in diverging microvascular bifurcations. The mechanical factors that determine which branch a red cell enters, including effects of red cells' finite size and deformability, will be investigated. 3. To incorporate the results of Specific Aims 1 and 2 into simulations of flow in microvascular networks, and to compare the predictions with observations. Mathematical and computational techniques will be used to develop these models. Emphasis will be placed on comparing the results with experimental findings, and on examining their physiological implications. This will be facilitated by well-established and active collaborations with experimental physiologists. The proposed research will contribute to understanding of microvascular blood flow in both normal and pathological states. Transport of oxygen and other materials to and from tissue depends on the distribution of flow and hematocrit within networks of microvessels. The mechanical processes governing this distribution are incompletely understood at present. Red cell deformability is impaired in a number of diseases. Previous studies have suggested that blood flow in non-uniform tubes. Thus, impaired flow in some diseases may result principally from the cells' reduced ability to traverse non-uniform pathways. The proposed research will provide quantitative predictions about these aspects of microvascular blood flow.